Preparation and method for effecting fat and lipid adsorption

ABSTRACT

The present invention relates to the aluminum hydroxide having a specific surface area of at least 350 m 2 , preferably at least 400 m 2 , per g. and to a process for its preparation. The aluminum hydroxide should be capable of absorbing at least 1 g of fat per g. of material. The aluminum hydroxide is preferably part of a pharmaceutical preparation.

This is a division of application Ser. No. 787,315 filed 10/15/85, U.S.Pat. No. 4,780,307.

BACKGROUND OF THE INVENTION

The present invention relates to an aluminum hydroxide having specificproperties.

Aluminum hydroxide is a known compound. Said known aluminum hydroxidehas so far been utilized for medication as an antacid drug, often incombination with other antacid drugs. From the literature, e.g. White etal., J.Pharm. Sci. 64, 468 (1976); Kerkhof, J.Pharm.Sci. 66,1533 (1977),it seems that the effect of said drug results apparently from theactivity of aluminum carbonate admixed therewith.

From the literature it is known that said commercially availablealuminum hydroxide has no dietary effect, i.e. it does not adsorbfoodstuffs and other nutritional factors. Thus, for example, thefollowing statements can be found in the literature:

1. "Relatively large doses of aluminum hydroxide cream did not alter thenitrogen or fat content of the feces of three normal dogs on a standarddiet." Beazell et al., Am.J.Digest.Dis. 5, 164-165 (1938).

2. "The results show that the ingestion of aluminum hydroxide waswithout appreciable effect upon the utilization of fat andcarbohydrate."

"Administration of aluminum hydroxide to a normal subject did notinterfere with the utilization of carbohydrate, fats or proteins of thediet."

Grondahl et al., Am.J.Digest.Dis. 12, 197-199 (1945).

3. "There appears to be no significant effect of alumina gel upon thetolerance curves of amino acids, ascorbic acid, glucose and neutralfats. Certainly in the case of neutral fats the results areunequivocal." Hoffman et al., Gastroenterology 6, 50-61 (1946).

4. "Absorption of foodstuffs and nutritional factors is not sufficientlydepressed to be important and the composition of the feces isunaffected." The Pharmacological Basis of Therapeutics, Goodman andGilman, 3rd.Ed., The Macmillan Company, N.Y. 1965, pp.995-997.

SUMMARY OF THE INVENTION

It has now surprisingly been found that there exists a specificaluminium hydroxide which does not show appreciable antacid activity.However, surprisingly, it adsorbs dietary lipids in a high efficiencyand increases their excretion.

The present invention thus consists in an aluminium hydroxide having aspecific surface area of at least 350 m² per g material. (hereinafter"the aluminium hydroxide").

The specific surface area in connection with the present invention isthe surface area measured by the method of Eltantawy et al., J.Soil.Sci.24, 232-238 (1973).

The aluminium hydroxide according to the present invention is capable ofadsorbing at least 1g of fat per g of the material.

The aluminium hydroxide according to the present invention has thefollowing properties:

a. a relatively large surface area;

b. strong adsorption of dietary lipids;

c. high capacity of fat adsorption;

d. after oral administration causes an increase in the excretion ofdietray lipids at the expense of the body intake; and

e. negligible antacid activity.

It is readily understood that the larger the specific surface area andthe higher the fat adsorption capacity the better the properties of thealuminium hydroxide according to the present invention. Thus, thespecific surface area is advantageously at least 400 m² /g and theadsorption capacity at least 1.5 g of fat/g of the aluminium hydroxide.

The aluminium hydroxide according to the present invention may beadministered as such, in the form of an aqueous suspension, in the formof a gel, etc.

The oral administration of the preparation comprising the aluminiumhydroxide according to the present invention causes a decrease of theactual caloric value of a concomitantly ingested food.

The present invention consists also in a process for the preparation ofthe aluminium hydroxide which comprises the neutralization of an acidicor basic solution of a suitable aluminium salt with a suitable base oran acid, respectively, with subsequent heating after the neutralizationreaction has been terminated.

The heating is advantageously performed at boiling temperature for atleast 1 hour after the neutralization reaction has been terminated.Sometimes the heating operation will be performed after filtration andwashing of the neutralization reaction mixture.

The process is preferably performed in diluted solutions.

The aluminium hydroxide is obtained by the above reaction either as aprecipitate or as a gel and may be utilized as such.

DESCRIPTION OF THE PREFERRED EMBODIMENT

It has been found that the stability of the aluminium hydroxide obatinedby said process may be increased by drying it under mild conditions,e.g. between 20°-40° C. The dried compound is then re-suspended.

As suitable salts for the above reaction may be considered AlCl₃,AlKSO₄, Al₂ (SO₄)₃, NaAlO₂ ; as acid HCl, H₂ SO₄, acetic acid, propionicacid, butyric acid and valeric acid or a mixture thereof; and as baseNaOH or KOH. However, it is readily understood that the presentinvention is not restricted to the use of the above salts, acids andbases.

The present invention will now be illustrated with reference to thefollowing Examples without being limited by them.

EXAMPLE 1

Two L of distilled water in which 100 ml of n-butyric acid and 32 ml ofn-valeric acid were dissolved, were neutralized in the cold by thegradual addition of an aqueous solution of 1 N NaOH which contained 0.5N NaAlO₂. The resulting aluminium hydroxide suspension was then boiledfor 2 hours and an aqueous solution of 1 N NaOH was added forneutralization as the pH dropped during heating. The precipitateobtained was filtered off and washed thoroughly with distilled water.The washed precipitate was resuspended in distilled water to a volume of800 ml and then let to dry at 37° C. Suspensions of about 5% aluminiumhydroxide in distilled water. (Hereinafter referred to as the 5%aluminium hydroxide) were prepared from the ground powder.

EXAMPLE 2

Two L of 0.5N of acetic acid in distilled water were neutralized in thecold by a gradual addition of an aqueous solution of 1N NaOH whichcontained 0.5N NaAlO₂. The resulting aluminium hydroxide suspension wasthen boiled for 2 hours and an aqueous solution of 1N NaOH was addedgradually for neutralization as the pH dropped during heating. Theprecipitate was filtered off and washed thoroughly with distilled water.The washed precipitate was resuspended in distilled water to a finalvolume of 800 ml, boiled for 11/2 hours and then let to dry in 37° C.Suspensions of the 5% of aluminium hydroxide in distilled water wereprepared from the ground powder.

EXAMPLE 3

10 g of pure aluminium metal were dissolved in 1 L of an aqueoussolution of 1N NaOH and then neutralized with an aqueous solution of 1NHCl at room temperature. The resulting aluminium hydroxide suspensionwas then boiled for 1 hour. The precipitate was then filtered off andwashed with distilled water. The washed precipitate was then resuspendedin distilled water to a final volume of 600 ml, yielding a suspension ofthe 5% aluminium hydroxide.

EXAMPLE 4

One L of 5% AlCl₃.6H₂ O in distilled water was neutralized with anaqueous solution of 2.5% NaOH at room temperature and then boiled for 1hour. The resulting aluminium hydroxide precipitate was filtered off andwashed with distilled water. The washed precipitate was then resuspendedwith distilled water to a final volume of 300 ml., yielding a suspensionof the 5% aluminium hydroxide.

EXAMPLE 5

Measurement of specific surface area

The specific surface area of aluminium hydroxide preparations wasdetermined by a gravimetric method, based on the retention of ethyleneglycol monoethyl ether(EGME), as described by Eltantaway I.M. and ArnoldP. W.(J.Soil Sci.24,232-238(1973)). The samples were first dried at 37°C., then ground and dried to constant weight over P₂ O₅.250 mg ofaluminium hydroxide powder were wetted with 1 ml of EGME in weighing cupand processed according to the conditions of method (c) as described byEltantawy and Arnold in the above paper. The specific surface area wascalculated using the theoretical value of 3.71×10⁻⁴ gof EGME for acomplete unimolecular layer coverage of 1 m².

The results obtained are summarized in Table I.

                  TABLE I                                                         ______________________________________                                        Aluminium hydroxide preparation                                                                  Specific surface area (m.sup.2 /g)                         ______________________________________                                        The aluminium hydroxide #1                                                                       735                                                        The aluminium hydroxide #2                                                                       611                                                        The aluminium hydroxide #3                                                                       413                                                        The aluminium hydroxide #4                                                                       538                                                        Alumina C (Aged)*  224                                                        Amphojel**          85                                                        ______________________________________                                         *Alumina C (Aged) is an aluminium hydroxide preparation manufactured by       Sigma Chemical Co.(St. Louis, Mo. U.S.A.) and described by the producer a     "An exceptionally active gel with high adsorptive capacity".                  **Amphojel is a suspension of aluminium hydroxide gel manufactured for        Wyeth Labs Inc.(Philadelphia Pa. USA) by Ayerst Labs Inc.(New York, NY        USA). It is used as an antacid.                                          

EXAMPLE 6

Demonstration of Antacid Capacity

1. Aluminium assay

5 g of the uniform suspension or gel prepared as described in any one ofExamples 1 to 4 were dissolved in 7 ml of conc. HCl (ca. 32%) by warmingon a water bath, and diluted to 100 ml in a volumetric flask. 10 ml ofthis solution were pipetted into a 250 ml beaker, 30 ml of a 0.025 Mdisodium edetate solution were then added and the mixture was thenneutralized with a 2 M sodium hydroxide solution to a methyl red endpoint and 75 ml of water were then added. After warming on a water bathfor 30 minutes and cooling to room temperature, 3 g of hexamine wereadded and the excess disodium edetate was back titrated with a ca. 0.025M lead (II) nitrate solution using xylenol orange as indicator. Thealuminium content expressed as % Al(OH)₃ was calculated by the formula:

    P=(0.025×30-M.sub.Pb ×V.sub.Pb)×78/W

where

M_(Pb) =the molarity of the lead (II) nitrate solution;

V_(Pb) =the volume of the lead (II) nitrate solution consumed in thenitration, in ml;

W=the exact weight in g of the substance tested; and

P=the % Al(OH)₃ in the preparation.

2. Neutralizing capacity

50 ml of 0.1 M hydrochloric acid solution were added to an aliquot ofabout 1 g of the uniform suspension or gel prepared as described in anyof Examples 1 to 4 and the resulting mixture was shaked continuously at37° C. for 1 hour. The excess acid was back titrated with 0.1 M sodiumhydroxide solution and the end point was determined either visually bythe colour change of bromophenol-blue indicator or potentiometrically atpH 3.5.

The acid neutralizing capacity, expressed in terms of milliequivalentsof acid consumed per 1 g of a 5% preparation, was calculated by thefollowing formula:

    (M.sub.HCl ×50-M.sub.NaOH ×V.sub.NaOH)×1/G×5/P,

where

M_(HCl) =the molarity of the hydrochloric acid solution;

M_(NaOH) =the molarity of the sodium hydroxide solution;

G=the exact weight in g of the tested substance;

V_(NaOH) =the volume of the sodium hydroxide solution consumed in thetitration, in ml; and

P=% Al(OH)₃ in the preparation obtained from the aluminium assay.

The results are summarized in Table II.

                  TABLE II                                                        ______________________________________                                        Aluminium hydroxide preparation                                                                  Acid neutralizing capacity                                 ______________________________________                                        The aluminium hydroxide #1                                                                       0.34                                                       The aluminium hydroxide #2                                                                       0.27                                                       The aluminium hydroxide #3                                                                       0.19                                                       The aluminium hydroxide #4                                                                       0.19                                                       Alumag             3.6                                                        ______________________________________                                    

The aluminium hydroxide is that according to the present invention.Alumag is a preparation of Zori Israel as described in Medic, 12, No.4,July-August, 1983, p.1.

EXAMPLE 7

Measurement of fat-adsorption capacity in vitro

The in vitro capacity of fat adsorption was determined using aradiolabelled triglyceride (TG). Glycerol tri[1-C¹⁴ ] oleate, purchasedfrom Amersham (Buckinghamshire, U.K.), was dissolved in pure olive oilto a final activity of about 10⁷ dpm/ml olive oil. A stable emulsion of1% TG was obtained by an intensive sonication of a mixture whichcontained 0.3g of the radiolabelled olive oil and 29.7 ml of a solutionof 4% oxibile extract in a 0.1M Tris-HCl buffer, pH 7.5. 1ml of thisemulsion was mixed with 1 ml of an aqueous suspension which containedvarious concentrations of the tested aluminium hydroxide preparation.After 5 min. incubation in room temperature, 8 ml. of distilled waterwere added and the mixture was let to stay at room temperature for 30minutes with frequent mixing. The entire mixture was then filteredthrough a Whatman No.41 filter paper and 0.5 ml of the filtrate wastransferred to a counting vial. 10 ml of a toluene scintillationsolution, containing 20% triton×100, were added to each vial. The amountof adsorbed TG was calculated by the relative radioactivity of thefiltrate as compared to that of the control system (containing noaluminium hydroxide). The capacity is defined as twice the amount ofgrams of TG adsorbed by 1 gram of aluminium hydroxide at 50% yield offat adsorption. The point of 50% yield of fat adsorption was derivedfrom the empirical isotherm proposed by Freundlich (W. J. Moore,Physical Chemistry 4th Ed., Longmans Green and Co.London,1962,pp.749-751).

The results are summarized in Table III:

                  TABLE III                                                       ______________________________________                                                            TG adsorption capacity                                    Aluminium hydroxide preparation                                                                   (grs TG/g Al(OH).sub.3),                                  ______________________________________                                        The Aluminium hydroxide #1                                                                        2.7                                                       The Aluminium hydroxide #2                                                                        3.2                                                       The Aluminium hydroxide #3                                                                        2.1                                                       The Aluminium hydroxide #4                                                                        1.9                                                       Alumina Cγ(Aged)                                                                            0.8                                                       Amphogel            0.05                                                      ______________________________________                                    

EXAMPLE 8

Demonstration of lipid adsorption in vitro.

1 ml of a preparation of 5% aluminium hydroxide as described in Example3 or 1 ml of a 5% suspension of a commercial (BDH) dry Al(OH)₃ indistilled water was mixed each with 1ml of a solution of 2% ox bileextract (Sigma) in 50 mM of Tris buffer, p.H 7.5, which contains alabeled lipid. The adsorption of the following lipids in each of theabove preparations was tested.

H³ Triloein (Amersham, 98% radiopure), H³ cholesterol (at least 96%radiopure); and H³ cholesteryl-lynoleyl-ether (97% radiopure).

The activity of the labeled compounds was adjusted to about 10⁵ dpm(disintegrations per minute) per system. Each assay was run induplicate.

After incubation for 1 hour at room temperature, with occasional mixing,each tube was centrifuged (1000 g) for 20 minutes and 1 ml of thesupernatent liquid was transferred to a counting vial. 10 ml of toluenesintillation solution containing 20% Triton×100 were added to each vial.

The adsorption of the lipids was calculated according to the followingequation:

% adsorption=[1-(dpm in the experiment/dpm in the control)]

The control system contains 1 ml of Tris buffer instead of the aluminiumhydroxide preparation. The results obtained are given in Table IV.

                  TABLE IV                                                        ______________________________________                                                  % adsorption of radiolabeled lipids                                                                  Cholesteryl-                                 adsorbant   Triolein  Cholesterol                                                                              linoleyl-ether                               ______________________________________                                        The 5% alu- 95%       99.3%      99.8%                                        minium hydroxide                                                              5% com.     0%        0%         46%                                          Al(OH).sub.3                                                                  Control     0%        0%          0%                                          ______________________________________                                    

EXAMPLE 9

Demonstration of inhibition of intestinal lipids absorption in vivo

The following materials and methods were used in this Example:

Animals

Three months old Balb/c male mice each weighing about 25 g were used forall experiments. The mice were raised in the animal facility of theHubert H. Humphrey Centre of The Medical School of the HebrewUniversity, Jerusalem. The mice were kept in temperature controlledrooms (about 24° C.) and fed the commercial laboratory chow diet.

Radiochemicals

Glycerol tri [1-C¹⁴ ]oleate (97% radiopure by TLC) obtained fromAmersham (Buckinghamshire, U.K.),

H³ triloeyl glyceryl ether, tritiated at C-2 of the glycerol carbonchain (at least 98% radiopure by TLC) prepared by the method describedin J.Lab.Radiopharm. 20, 269 (1983).

Test meal

After the evaporation of the organic solvent, each radiochemical wasdissolved in olive oil and admixed therewith. The average dose per mousewas 0.05 ml of test meal containing about 10⁵ dpm of the tritiatedcompound.

In the triolein ester:trioleyl ether mixture the C¹⁴ :H³ ratio was about1.5-2.

0.05 ml of olive oil-vehicle test meal was introduced by a gastic tube(intramedic polyethylene tubing PE90 or PE50, Clay Adams, Inc., NewYork) connected to a 1 ml syringe through a Teflon catheter. In order toavoid bowel perforation the leading edge of the tube was wrapped with ashort segment of a Silastic tube (Dow Corning Corp., Midland, Michigan).The administered amount was calculated precisely by syringe weighing.

Fecal collection.

The method of anal cups described by Ryer et al., Lab. Anim. Sci.21, 942(1971) for rats was adapted for use in mice. Light, flexible cellulosenitrate tubes (ultracentrifuge tubes, Beckman, Palo Alto) of 5/8"dia.×2.5" height were found to be most suitable for this experiment. Arose shaped opening of about 0.5 cm diameter was drilled in 1.5-2 cmbelow the upper part of the tube. The tail was slipped through this holeand the tube was fitted to the mice body, leaving the penis outside. Thetail was then taped to the tube. Each tube was weighed before and afterthe fecal collection and the harvest was transferred to a 50 ml glasstube for lipid extraction.

Experimental design

After an overnight fast, each mouse received a mixture of radioactiveadsorbable lipid alongside with the nonadsorbable labeled analog in atotal volume of 0.05 ml of olive oil, as described above. The feedingwas performed by stomach intubation under slight ether anesthesia. Forstudying the effect of the various aluminium hydroxide preparations 0.25ml of a 5% suspension of the preparation according to the presentinvention (four batches) in saline was introduced by a gastric tube 30minutes prior to the introduction of the test meal. Another dose of 0.25ml of the preparation was administered immediately after the test mealhad been administered. In a similar manner the effect of an Alumagpreparation was assayed.

The anal cup was then inserted and the animals were kept in separatedcages, supplied with the regular diet, ad libidum. The fecal collectionwas terminated after 24 hours. The entire content of the removed cupswas analysed.

Lipid extraction

An aqueous solution of 10% sodium dodecyl sulfate (SDS) was added to thefeces in a ratio of 1.5 ml/1 g. (Usually a standard volume of 3 ml ofSDS 10% was added to a 24 hour fecal collection). In order to achievebetter dispersion, the preparations together with the detergent wereincubated overnight at 37° C. and were admixed from time to time. Theprocedure of Bligh and Dyer (Can.J.Biochem.Physiol.37,911 (1959) forlipid extraction was applied to the fecal suspension (which usually washomogenous). Assuming that the regular daily collection of mouse fecesplus 3 ml of SDS 10% contains about 4 ml of water. Slight variations ofthe water content should not interfere with the extraction procedure).Samples in duplicate, of 1 ml each, were taken from the separatedchloroform phase. After complete evaporation of the solvent, 10 ml oftoluene scintillation solution, which contained 20% of Triton×100 wereadded to the vials.

Calculation of absorption

The percentage of lipid absorption was calculated according to theisotope ratio method:

% lipid absorbed =[1-(absorbable to nonabsorbable isotope ratio in thefecal collection/absorbable to nonabsorbable isotope ratio in the testmeal)]×100.

The results obtained are summarized in Table V.

                  TABLE V                                                         ______________________________________                                        Oral administration                                                                             % Triglycerides excreted*                                   ______________________________________                                        Saline (Control)   2.8% + 0.8 (19)                                            The aluminium hydroxide #1                                                                      51% ± 6.4 (8)                                            The aluminium hydroxide #2                                                                      49% ± 7.9 (6)                                            The aluminium hydroxide #3                                                                       33% ± 6.1 (18)                                          The aluminium hydroxide #4                                                                      22% ± 9.1 (6)                                            Alumag            3.9% ± 1.1 (9)                                           ______________________________________                                         *mean ± S.E.M.(standard error of the mean) as determined by the isotop     ratio method;                                                                 (n) number of mice in each group                                              % excreted = 100 - % absorbed                                            

EXAMPLE 10

Demonstration of body weight reduction by chronic administration of thealuminium hydroxide

Albino, Israeli male mice, weighing around 30g, were selected for theexperiment. Three equal groups, of 10 mice each, were fed daily for 6hours on a regulr chaw diet. Prior to the beginning of the meal, theanimals received by way of a gastric tube either 0.5 ml of saline(=group 1), or 0.5 ml of 6% suspension of the bile acids sequestingagent cholestyramine (=group 2), or 0.5 ml of 6% suspension of thealuminium hydroxide, preparation #2 (=group 3). The individual bodyweight was measured daily and the experiment lasted for a period of 75days. The relative change in body weight in each group was compared tothat of the control group (group 1).

While almost no difference in the pattern of body weight changes wasobserved between group 1 and group 2, the animals which received thealuminium hydroxide preparation (group 3) showed a significant reductionin their relative body weight:

After two weeks from the beginning of the experiment, their body weightwas 7% lower then that of the controls and after 8 weeks the decreasereached was about 10%. It should be stressed that there was a slightincrease (about 10%) in the food consumption by the animals of group 3,as compared to groups 1 and 2.

The average daily dietary intake under these experimental conditions wasequivalent to about 300 calories per kg body weight.

I claim:
 1. Pharmaceutical preparation for fat and lipid adsorption uponadministration thereof, said preparation being in a form for oraladministration and providing a fat and lipid adsorption effective amountof aluminium hydroxide having a specific surface area of at least 400 m²per g and having a high degree of adsorption of dietary lipids and fatswhile having negligible antacid activity,said aluminium hydroxide beingcapable of adsorbing at least 1 g of fat per g of said aluminiumhydroxide, and said preparation being in the form of an aqueoussuspension, whereby ingestion of said preparation causes excretion ofdietary lipids.
 2. Pharmaceutical preparation according to claim 1wherein said aluminium hydroxide is capable of adsorbing at least 1.5 gof fat per g of the aluminium hydroxide.
 3. Pharmaceutical preparationaccording to claim 1 wherein said aluminium hydroxide has a specificsurface area of about 413 to about 735 m² /g.
 4. Pharmaceuticalpreparation according to claim 1 wherein aluminium hydroxide has an acidneutralizing capacity of about 0.19 to about 0.34 milliequivalents ofacid consumed per g of preparation.
 5. Pharmaceutical preparationaccording to claim 1 wherein said aluminium hydroxide has a fatadsorbing capacity of about 1.9 to about 3.2 g of fat per g of aluminiumhydroxide.
 6. The preparation of claim 1, wherein said preparation is inthe form of about a 5% aqueous suspension.
 7. Pharmaceutical preparationfor fat and lipid adsorption upon administration thereof, saidpreparation being in a form for oral administration and providing a fatand lipid adsorption effective amount of aluminium hydroxide having aspecific surface area of at least 400 m² per g and having a high degreeof adsorption of dietary lipids and fats while having negligible antacidactivity.said aluminium hydroxide being capable of adsorbing at least 1g of fat per g of said aluminium hydroxide, and being prepared by thesteps of neutralizing an acidic or basic solution of an aluminium saltwith a base or an acid in a non-toxic, aqueous medium, after theneutralization reaction has been terminated, subsequently heating thethus-neutralized solution by boiling, and preparing an aqueoussuspension from residue after said boiling, whereby ingestion of saidpreparation causes excretion of dietary lipids.
 8. The preparation ofclaim 7, wherein about a 5% aqueous suspension is prepared from theresidue after said boiling.
 9. Method of effecting fat and lipidadsorption, which comprises administering a fat and lipid adsorptioneffective amount of aluminium hydroxide having a specific surface areaof at least 400 m² per g and having a high degree of adsorption ofdietary lipids and fats while having negligible antacid activity, saidaluminium hydroxide being capable of adsorbing at least one g of fat perg of aluminium hydroxide.whereby said administration causes excretion ofdietary lipids.
 10. Method according to claim 9 wherein said aluminiumhydroxide is capable of adsorbing at least 1.5 g of fat per g ofaluminium hydroxide.
 11. Method according to claim 9 wherein saidaluminium hydroxide has a specific surface area of about 413 to about735 m² /g.
 12. Method according to claim 9 wherein said aluminiumhydroxide has an acid neutralizing capacity of about 0.19 to about 0.34milliequivalents of acid consumed per g of a preparation including saideffective amount of aluminium hydroxide.
 13. Method according to claim 9wherein said aluminium hydroxide has a fat adsorbing capacity of about1.9 to about 3.2 g of fat per g of aluminium hydroxide.
 14. Methodaccording to claim 9 wherein said aluminium hydroxide is in the form ofa gel.
 15. Method according to claim 9 wherein said aluminium hydroxideis in the form of a precipitate.